The purpose of this competing renewal application is to evaluate the impact of evolving drug use patterns, as well as a range of social, structural, and environmental factors, on HIV incidence, morbidity, and mortality among a cohort of HIV-negative injection drug users (IDU) in Vancouver, Canada. We propose to undertake this work in a setting where a steady growth in methamphetamine injection has become an increasing concern. The proposed research involves the continuation of the Vancouver Injection Drug Users Study (VIDUS), which is among the longest-standing cohort studies in North America. Since 1997, this study has led to more than 120 peer-reviewed publications in the area of public health, HIV/AIDS, and injection drug use. Vancouver, Canada, is unique in North America and is ideally suited to the proposed research questions for several reasons. First, the city is home to one of the most explosive HIV epidemics ever documented among IDU in the developed world, with HIV incidence peaking at 18 per 100 person-years in 1997 and persistently elevated HIV rates continuing up to 2007. Second, like many West Coast cities, Vancouver is in the midst of a massive growth in the use of methamphetamine and is also seeing a dramatic increase in methamphetamine injection. Third, Vancouver is unique in having an exceptionally large and visible street-based drug market and a large network of single-room occupancy hotels (SROs). We seek to build upon our past work focused on individual risk factors and health service use by investigating the impact of various social, structural, and environmental factors on HIV risk behavior, HIV incidence, morbidity, mortality, and hospital utilization among IDU. Herein we propose to continue our cohort-based approach involving semi-annual follow-up of 1000 HIV-negative IDU. We also propose to continue taking advantage of the universal healthcare system and centralized health data in British Columbia by linking participant data to a range of healthcare databases. Our proposed continuation of cohort-based research offers an ideal opportunity to examine the impact of evolving drug use patterns, as well as the impact of various social, structural, and environmental factors on the natural history of injection drug use. Given that methamphetamine use emerged on the West Coast, our investigation of rising methamphetamine injection could provide important information and early warning to other North American settings. In sum, through the continuation of VIDUS, we aim to address several urgent global health challenges and inform the development of a range of policies and interventions.